Measles is a highly contagious, human disease that is spread by the respiratory route and remains among the top 10 causes of deaths (197,000 in 2007) due to infectious diseases and the second most common cause of death due to vaccine-preventable disease in children under the age of 5 years. Simple, low-cost, needle-free alternative vaccination strategies may help to significantly reduce the severe global impact of measles in terms of mortality and morbidity. The vast majority of vaccines are delivered by injection, including measles vaccine. Needle-free vaccinations would also help to overcome many of the problems associated with injections, including accidental disease transmission (e.g., hepatitis, and HIV) due to needle-stick injuries or improper/unsafe use of injectables, biohazardous sharps waste disposal, pain at injection site, and need for skilled healthcare workers. In this project we propose to test the hypothesis that sublingual measles vaccine is a viable alternative to the injectable vaccine. In Specific Aim 1, we will develop sublingual measles vaccine formulations with the goals of achieving desired wafer physical properties (e.g., wafer cohesiveness, and target dissolution/disintegration rates), acceptably recovering vaccine potency from the wafer, and understanding the effect of saliva on vaccine virus titer. In Specific Aim 2, measles vaccine dry wafer formulations and liquid measles vaccine droplets will be administered sublingually to cotton rats and compared to subcutaneous injection of the vaccine in terms of their ability to generate an immune response. In Specific Aim 3, a measles vaccine dry wafer formulation will be administered sublingually to measles-naive rhesus macaques. Sera and lavage samples will be analyzed for measles-specific antibody and T cell responses. Lavage samples will also be evaluated for measles RNA. A successful outcome to this project opens up a number of avenues for follow-on research including: 1) conducting a challenge study of the sublingually immunized and negative control macaques one year after vaccination to verify protective immunity;2) studies with green fluorescent protein (GFP) labeled measles vaccine virus administered sublingually to elucidate the sites of infection and replication;3) extension of this sublingual vaccination approach to mumps and rubella to develop a single trivalent sublingual vaccine;4) exploration of sublingual vaccination for other infectious diseases such as influenza, human papillomavirus, yellow fever, and anthrax. PUBLIC HEALTH RELEVANCE: Measles is the second most fatal vaccine-preventable disease, with 197,000 deaths globally in 2007 (mostly children under 5 years old). Alternative needle-free, mucosal immunization strategies may help reduce the severe impact of measles in global health, and help to overcome many of the problems associated with needle and syringe injections, which are how most vaccines are administered, including measles vaccine. We propose to develop sublingual measles vaccine formulations and to test these in appropriate animal models (cotton rats and rhesus macaques) for immunogenicity. Sublingual vaccination may be broadly applicable to a number of other infectious diseases, including mumps, rubella, influenza, human papillomavirus, yellow fever, and anthrax.